Format

Send to

Choose Destination
Leukemia. 2018 Mar;32(3):828-836. doi: 10.1038/leu.2017.280. Epub 2017 Sep 5.

C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation.

Author information

1
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
2
Department of Molecular Biology, Faculty of Science, RIMLS, Radboud University, Nijmegen, The Netherlands.
3
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
4
Max Planck Institute for Molecular Genetics, Berlin, Germany.
5
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
6
Pediatric Oncology/Hematology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
7
Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
8
MLL Munich Leukemia Laboratory, Munich, Germany.

Abstract

Overexpression of the BRE (brain and reproductive organ-expressed) gene defines a distinct pediatric and adult acute myeloid leukemia (AML) subgroup. Here we identify a promoter enriched for active chromatin marks in BRE intron 4 causing strong biallelic expression of a previously unknown C-terminal BRE transcript. This transcript starts with BRE intron 4 sequences spliced to exon 5 and downstream sequences, and if translated might code for an N terminally truncated BRE protein. Remarkably, the new BRE transcript was highly expressed in over 50% of 11q23/KMT2A (lysine methyl transferase 2A)-rearranged and t(8;16)/KAT6A-CREBBP cases, while it was virtually absent from other AML subsets and normal tissues. In gene reporter assays, the leukemia-specific fusion protein KMT2A-MLLT3 transactivated the intragenic BRE promoter. Further epigenome analyses revealed 97 additional intragenic promoter marks frequently bound by KMT2A in AML with C-terminal BRE expression. The corresponding genes may be part of a context-dependent KMT2A-MLLT3-driven oncogenic program, because they were higher expressed in this AML subtype compared with other groups. C-terminal BRE might be an important contributor to this program because in a case with relapsed AML, we observed an ins(11;2) fusing CHORDC1 to BRE at the region where intragenic transcription starts in KMT2A-rearranged and KAT6A-CREBBP AML.

PMID:
28871137
DOI:
10.1038/leu.2017.280

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center